title: Metallothionein 3: an androgen-upregulated gene enhances cell invasion and tumorigenesis of prostate carcinoma cells.
abstract: BACKGROUND
  Metallothioneins (MT1, MT2, MT3, and MT4) are regarded as modulators regulating a number of biological processes including cell proliferation, differentiation, and invasion. We determined the effects of androgen, cadmium, and arsenic on MT1/2 and MT3 in prostate carcinoma cells, and evaluated the functional effects of MT3 on cell proliferation, invasion, and tumorigenesis.
  
  
  METHODS
  We determined the expression of MT1/2 and MT3 in prostate carcinoma cells by immunoblotting assays or real-time reverse transcription-polymerase chain reactions. The effects of ectopic MT3 overexpression or MT3-knockdown on cell proliferation, invasion, and tumorigenesis were determined by (3) H-thymidine incorporation, matrigel invasion, and murine xenograft studies. The effects of androgen, cadmium, and arsenic on target genes were assessed using immunoblotting and reporter assays.
  
  
  RESULTS
  Androgen, cadmium, and arsenic treatments enhanced gene expression of MT1/2 and MT3 in prostate carcinoma LNCaP cells. Results of immunohistochemical staining indicated MT3 overexpression was found predominantly in the nuclear areas of PC-3 cells overexpressing MT3. Overexpression of MT3 significantly increased cell proliferation, invasion, and tumorigenic activities in PC-3 cells in vitro and in vivo. MT3 overexpression downregulated the gene expressions of N-myc downstream regulated gene 1 (Ndrg1) and maspin, and attenuated blocking effects of doxorubicin in PC-3 cells on cell proliferation. MT3-knockdown enhanced Ndrg1 and maspin expressions in LNCaP cells.
  
  
  CONCLUSIONS
  The experiments indicate that MT3 is an androgen-upregulated gene, and promotes tumorigenesis of prostate carcinoma cells. The downregulation of Ndrg1 and maspin gene expressions appears to account for the enhancement of proliferative and invasive functions of MT3 in PC-3 cells.
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Chung
authors.forename: Hsin-Ching
authors.initials: HC
authors.lastname: Sung
authors.forename: Tsui-Hsia
authors.initials: TH
authors.lastname: Feng
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Lee
authors.forename: Phei-Lang
authors.initials: PL
authors.lastname: Chang
authors.forename: Ke-Hung
authors.initials: KH
authors.lastname: Tsui
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000378:metabolism; D002104:Cadmium / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D024861:Genetic Enhancement; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008668:Metallothionein / Q000235:genetics*; D000090023:Metallothionein 3; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D015843:Serpins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000728:Androgens; D001151:Arsenic; D002104:Cadmium; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008668:Metallothionein; D000090023:Metallothionein 3; D015843:Serpins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C000715430:Mt3 protein, mouse; C085344:SERPIN-B5
keywords: Ndrg1; androgen; maspin; metallothionein; prostate